Dendritic cells (“DC”s) are potent antigen-presenting cells (“APC”s) in the immune system. It has been shown that DCs provide all the signals required for T cell activation and proliferation. These signals can be categorized into two types. The first type, which gives specificity to the immune response, is mediated through interaction between the T-cell receptor/CD3 (“TCR/CD3”) complex and an antigenic peptide presented by a major histocompatiblity complex (“MHC”) class I or II protein on the surface of APCs. This interaction is necessary, but not sufficient, for T cell activation to occur. In fact, without the second type of signals, the first type of signals can result in T cell anergy. The second type of signals, call costimulatory signals, is neither antigen-specific nor MHC-restricted, and can lead to a full proliferation response of T cells and induction of T cell effector functions in the presence of the first type of signals.
Costimulatory signals are generated by interaction between receptor-ligand pairs expressed on the surface of APCs and T cells. One exemplary receptor-ligand pair is one of the B7 costimulatory molecules on the surface of DCs and its counter-receptor CD28 or CTLA-4 on T cells (Freeman et al., Science 262:909-11 (1993); Young et al., J. Clin. Invest. 90:229 (1992); Nabavi et al., Nature 360:266 (1992)).
DCs are minor constituents of various immune organs such as spleen, thymus, lymph node, epidermis, and peripheral blood. For instance, DCs represent merely about 1% of crude spleen (Steinman et al., J. Exp. Med. 149:1 (1979) or epidermal cell suspensions (Schuler et al., J. Exp. Med. 161:526 (1985); and Romani et al., J. Invest. Dermatol. 93:600 (1989)), and 0.1-1% of mononuclear cells in peripheral blood (Freudenthal et al., Proc. Natl. Acad. Sci. USA 87:7698 (1990)). Methods for generating dendritic cells from peripheral blood or bone marrow progenitors have been described (Inaba et al., J. Exp. Med. 175:1157 (1992); Inaba et al., J. Exp. Med. 176:1693-1702 (1992); Romani et al., J. Exp. Med. 180:83-93 (1994); and Sallusto et al., J. Exp. Med. 179:1109-1118 (1994)).